Silver(I) complexes containing N-heterocyclic carbene azole drugs: Synthesis, characterization, cytotoxic activity, and their BSA interactions

Cancer is one of the main public health problems globally, there is a public demand for better drugs. Rational strategies or approaches are used to improve the success of drug discovery. Our strategy was to the repurposing of well-known antifungal agents as potential anticancer drugs, such as Clotrimazole (CTZ) and Ketoconazole (KTZ). We prepared the respective iodide imidazolium salt L1: (CTZ-Me)I and L2: (KTZ-Me)I to be the intermediates toward the synthesis of its respective NHC ligand and achieve the respective silver(I)-monoNHC and silver(I)-bisNHC derivatives: [Ag(L1)I] (1), [AgI(L2)] (2) [Ag(L1)2]I. (3), [Ag(L2)2]I. (4), as well as their corresponding coordination compounds [Ag(CTZ)2]NO3 (5) and [Ag(KTZ)2]NO3 (6) where these ligands (CTZ and KTZ) coordinate to silver through the N-imidazole atom. These compounds (L1, L2 and complexes 1-6) exhibited significant activity against the tested cancer cell lines (B16-F1, murine melanoma strains and CT26WT, murine colon carcinoma). The silver(I) complexes were more active than the free ligands, complexes 2 and 4 being the most selective in B16-F1 cancer cell line. Two possibles biological targets such as DNA and albumin were examined for the observed anticancer activity. Results show that DNA is not the main target, however, the interactions with albumin suggest it can transport/delivery the metal complexes.

Automated summary

Cancer is a global public health problem, and there is a demand for better drugs. The repurposing of well-known antifungal agents, such as Clotrimazole and Ketoconazole, as potential anticancer drugs was investigated. Silver(I) complexes derived from these agents showed significant activity against cancer cell lines and had higher selectivity than the free ligands. The potential biological target for the observed anticancer activity was found to be albumin, suggesting its role in transporting/delivering the metal complexes.